A dose-escalation study of HP501, a highly selective URAT1 inhibitor, in male Chinese patients with hyperuricemia

HP501 is a highly selective renal urate transporter 1 (URAT1) inhibitor used for treating hyperuricemia. This study aimed to evaluate the tolerability, pharmacokinetics, and pharmacodynamics of HP501 in male Chinese patients. Patients with hyperuricemia were sequentially assigned to receive oral doses of HP501 (30, 50, 60, 90, and 120 mg) as a single dose on Day 1 and as once-daily doses from Days 4 to 13. Safety, pharmacokinetic, and pharmacodynamic data were collected. Multiple oral doses of HP501 were well-tolerated in all the cohorts. The most common adverse events (≥ 10% of patients) of any grade regardless of drug relationship were gout flare (14 patients, 25.93%), diarrhea (12 patients, 22.22%), elevated ALT (8 patients, 14.81%), hypertriglyceridemia (7 patients, 12.96%), dry mouth (7 patients, 12.96%) and oral ulcer (7 patients, 12.96%). All adverse events were mild or moderate. The Cmax and exposure (AUC) of HP501 was approximately dose-proportional between 30 and 120 mg. A dose-dependent serum uric acid (UA)-lowering effect was observed in the dose range of 30 to 60 mg and the serum UA lowering effect was similar between 90 and 120 mg on day 13, indicating that the maximal serum UA lowering effect of HP501 was achieved at 90 mg in the patients with hyperuricemia. In conclusion, the tolerability, pharmacokinetics, and pharmacodynamics supported 90 mg HP501 for subsequent clinical studies of this highly selective URAT1 inhibitor. Clinical Trial registration: No. CTR20212259 (http://www.chinadrugtrials.org.cn/) was registered in September 2021, and No. CTR20222257 was registered in September 2022.


Patients
The inclusion criteria included the following: hyperuricemic patients aged 18-65 years old with or without gout, diagnosed according to the Chinese guideline 13 ; serum UA levels ≥ 540 μmol/L for patients with asymptomatic hyperuricemia or ≥ 480 μmol/L for patients with gout.
The main exclusion criteria included the following: patients with a body mass index (BMI) below 18 or over 30 kg/m 2 ; patients with a known history of allergy to the preparations of HP501; patients who had participated in the prior clinical trials of HP501; patients who had administrated serum UA-lowering drugs in the 14 days before enrollment; patients who had used any drug or food that can either affect CYP2C8 or CYP2C9 in the 14 days before enrollment; patients with a peptic ulcer; patients with serious cardiac disorders; patients with abnormal laboratory test results, such as an estimated glomerular filtration rate < 60 mL/min/1.73m 2 , alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2 × upper limit of normal (ULN), and hemoglobin < 90 g/L.

Statistical analysis
SAS software (version 9.4; SAS Institute, Cary, NC, USA) was used for statistical analyses.Demographic, pharmacokinetic, pharmacodynamic, and safety data were summarized as descriptive statistics.The safety analysis was performed on the safety population, which included patients who received at least 1 dose of HP501.χ 2 test was used to compare the incidences of AEs among the cohorts.The pharmacokinetic analysis was performed in patients who received HP501 and had at least 1 post-dose measurement of plasma HP501.The pharmacodynamic analysis was performed in patients who received HP501 and had at least 1 post-dose measurement of serum UA level.The sample size of this study was determined empirically.Cohorts of 8-12 patients were considered adequate to initially characterize the safety, pharmacokinetic and pharmacodynamic profiles of HP501.Dose proportionality of pharmacokinetic and pharmacodynamic parameters of HP501 was analyzed using a power model by means of a regression analysis with the log-transformed end point as a response and log-dose as a fixed effect.Dose proportionality was supported if the 95% confidence interval (CI) for the slope β fell completely within 0.84-1.16(the criterion interval: 1 + [ln (0.80)/ln(r)], 1 + [ln (1.25)/ln(r)], r = the highest dose/the lowest dose) 14 .Statistical significance was defined based on a two-tailed p value of < 0.05.

Ethical approval
The study protocol and informed consent forms were reviewed and approved by the Institutional Ethics Committees of the Affiliated Hospital of Southwest Medical University (Luzhou, China; approval number: L2022040) and Chengdu Fifth People's Hospital (Chengdu, China; approval number: 2021-013-01).The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

Consent to participate
All participants provided written informed consent before participation in the study.

Demographics
In the present study, five dose cohorts were used, and 163 patients were screened.Of these 163 patients, 109 were excluded from the study (Fig. 1).Finally, 54 male patients with hyperuricemia aged between 18 and 56 years were included in this study.The 54 patients were sequentially assigned to five dose cohorts (30 mg, 50 mg, 60 mg,  1.

Pharmacokinetic outcomes
The mean plasma concentration-time curves for HP501 are shown in Fig. 2. Following single dose of 30-120 mg HP501, T max of HP501 occurred at 3.00-4.50h postdose, suggesting rapid absorption of HP501.

Pharmacodynamic outcomes
The mean percentage changes in serum UA levels from baseline in the five cohorts are shown in Fig. 4. The UA lowering effect of HP501 was increased with an increase in the administration dose from 30 to 90 mg.However, the curve of the 120 mg cohort almost coincided with that of the 90 mg cohort, indicating that the serum UAlowering effect was similar between the 90 and 120 mg cohorts.Thus, the serum UA lowering effect of HP501 might be saturated at the 90 mg dose level in patients with hyperuricemia.
The lowest serum UA level below 360 μmol/L was observed in 2 out of 10 patients (20.00%) in the 30 mg cohort, 5 out of 10 patients (50.00%) in the 50 mg cohort, 5 out of 10 patients (50.00%) in the 60 mg cohort, 10 out of 12 patients (83.33%) in the 90 mg cohort and 9 out of 12 patients (75.00%) in the 120 mg cohort (Table 6).Comparing to 30-60 mg cohorts, 90 mg cohort seemed to have a higher proportion of patients achieving a serum UA level ≤ 360 μmol/L.But the proportion of such patients in the 120 mg cohort was not increased continuously.The 90 mg and 120 mg had similar proportions of patients achieving a serum UA level ≤ 360 μmol/L.
The above results indicate that the serum UA decline was saturated at the 90 mg dose level in patients with hyperuricemia.Owing to the pharmacodynamic outcomes of 30-120 mg cohorts, the UA-lowering effect of HP501 was not expected to increase when the administration dose was over 90 mg.Thus, the 150 mg and 180 mg cohorts were not included in this study.

Discussion
The present study was conducted based on a former phase I/IIa trial of HP501 12 with the aim of determining a more suitable administration dose for the phase III trial of HP501.We found that multiple oral doses of 30-120 mg HP501 were well tolerated.Pharmacokinetic analysis that HP501 exposure increased with an increase in the administration dose from 30 to 120 mg.However, pharmacodynamic analysis revealed that serum UA lowering might be saturated at the 90 mg dose level in patients with hyperuricemia.The UA-lowering effect of HP501 was not expected to increase when the dose exceeded 90 mg.Thus, the 150 mg and 180 mg cohorts were not studied further.
In the present study, we found that patient with hyperuricemia was well tolerated at a daily dose of 30-120 mg of HP501.No SAEs were reported in either of the cohorts.The most common AEs reported in this study were gout flare, diarrhea, elevated ALT, hypertriglyceridemia, dry mouth and oral ulcer.The incidences of AEs among the 5 active cohorts were not significantly different.
Hepatocellular injury is one of the most common treatment-related AEs associated with uricosuric drugs 15 .During the phase I/IIa trial of HP501, hyperuricemic patients received 45 mg of HP501 for 10 days, and 2/10 and 3/10 patients had elevated AST and ALT levels, respectively 12 .Another phase I trial evaluating the drug-drug interaction of HP501, febuxostat, and colchicine, showed that 1 out of 14 patients who received 40 mg HP501 once daily for 7 days had elevated ALT levels 16 .Due to the previous studies of HP501, we specially focused on the hepatotoxicity of HP501 in this study.We found that only one patient received ≤ 60 mg of HP501 (1/10 in 30 mg cohort) had elevated ALT levels.However, 3/12 patients in the 90 mg cohort and 4/12 in the 120 mg cohort experienced elevated ALT levels.High dose levels of HP501 seemed to have an increasing trend of hepatic injury.Fortunately, similar to the findings of Wang's study 12 , we found that the liver enzyme activities could return to normal values no more than half a month after the AEs were found without any interruption, indicating the hepatic injury was mild and reversible.
Dry mouth was the most common AE of HP501, as observed in the study conducted by Wang et al. 12 .Our study also observed that of 3/12 patients in the 90 mg cohort and 4/12 in the 120 mg cohort had dry mouth during the study period.AEs associated with dry mouth were mild and temporary.The patient did not require any interruptions.
Nephrotoxicity is regarded as a potential risk factor for URAT1 inhibitors 17,18 because the increased excretion of UA may lead to its microcrystallization in the renal tubule, causing epithelial injury 7,19 .About 24.30% of patients who received lesinurad (a URAT1 inhibitor developed by Ardea Biosciences) monotherapy had increased serum creatinine 11 .Verinurad, a high-affinity inhibitor of the URAT1 transporter, was reported to elevate serum creatinine 1.5 times to baseline level in 17.1% Japanese patients with hyperuricemia 20 .In the phase I/IIa trial of HP501, no renal-related AEs were observed at study doses ranging from 3 to 60 mg 12 .In the present study, the 90 and 120 mg cohorts showed one case with increased serum creatinine levels, respectively.Of note, the two patients had slightly higher serum creatinine levels at baseline, and the increase in serum creatinine during the study period did not exceed the 1.5 times of normal values.Thus, we could not determine whether the increase in serum creatinine levels in the two cases was related to the study drug.Further studies with longer duration are required to answer this question.
Except for 14 cases of gout flares, all other reported AEs in the five cohorts were mild.Our data showed that 120 mg did not reach the minimum intolerable dose of HP501.The safety of HP501 demonstrated in this study supports the use of 90 or 120 mg of HP501 in subsequent clinical trials.
Our pharmacokinetic results showed that plasma exposure (AUC and C max ) of HP501 was approximately dose-proportional between 30 and 120 mg in both SAD and MAD.In the phase I/IIa trial, following hyperuricemic patients treated with 45 mg HP501 once daily for 10 days, the C max of serum HP501 was 3.9 ± 1.0 μg/mL and AUC 0-24 h was 50.9 ± 10.5 h*μg/mL 12 .Compared to these historical data, hyperuricemic patients receiving 50-120 mg of HP501 for 10 days had a much higher plasma exposure to HP501 in this study.The mean t 1/2 of HP501 at steady state was 11.77-13.47h, which is consistent with previous studies 12,16 .Following daily dosing of HP501 for 10 days, the mean R ac was 1.282-1.413 in the 5 cohorts, indicating no obvious accumulation of HP501 during the study period.In the dose-proportionality analysis, the 90% CI of the β values of pharmacokinetic parameters did not completely fall in the criterion interval 0.84-1.16.However, due to the small sample size of this study and the crossover between the 90% CI of β value and the range, it cannot be concluded whether HP501 possesses linear or nonlinear pharmacokinetic characteristics in the dose range of 30-120 mg.
Our pharmacodynamic results did not correspond with the pharmacokinetic results.The curves of serum UA change showed that UA lowering effect of HP501 was increased with an increase in the administration dose from 30 to 90 mg.However, the curve of the 120 mg cohort almost coincided with that of the 90 mg cohort, indicating that the serum UA-lowering effect was similar between the 90 and 120 mg cohorts.The dose-proportionality analysis found that values of β of ΔC max % and ΔAUC 0-24 h did not fall in the criterion interval 0.84-1.16,indicating HP501 did not possess linear pharmacodynamic characteristics in the dose range of 30-120 mg.The target of serum UA level for the management of hyperuricemia is ≤ 360 μmol/L in consideration of the solubility of urate crystals 21,22 .In this study, 90 mg cohort seemed to have a higher proportion of patients achieving a serum UA level ≤ 360 μmol/L, comparing to 30-60 mg cohorts.However, the percentages of patients achieving a serum UA level ≤ 360 μmol/L were similar between the 90 and 120 mg dose cohorts.These results indicate that the decline of serum UA by HP501 might be saturated at the 90 mg dose level in patients with hyperuricemia.Receptor saturation maybe related to this phenomenon.Based on the pharmacodynamic results, the UA-lowering effect of HP501 was not expected to increase when the administered dose exceeded 90 mg.A once-daily dose of 90 mg HP501 was recommended for subsequent studies.Thus, the 150 mg and 180 mg cohorts were not included in this study.
The present study had several limitations.First, the total treatment duration was short.Further studies are required to evaluate the long-term activity and safety of HP501.Second, it has been reported that the prevalence of hyperuricemia is about 4.9% in Chinese women, which is slightly less prevalent than that in Chinese men (4.9% vs. 7.9%) 23 .This study did not enroll female patients with hyperuricemia.The published literature has shown that the efficacy and safety of treatments for female patients with hyperuricemia cannot be extrapolated from studies that predominantly include males 24 For example, data from the febuxostat versus Allopurinol Streamlined Trial (FAST) showed that female patients with gout who received XOIs had a higher rate of comorbid cardiovascular risk factors than male patients 25 .Therefore, future studies should evaluate the safety and efficacy of HP501 in female patients.To evaluate the safety and efficacy of HP501 comprehensively, a phase II trial of HP501 is undergoing (CTR20230489), which is scheduled to enroll 120 patients.Finally, the sample size was small and the safety and efficacy of HP501 could not be comprehensively evaluated.

Conclusion
In summary, multiple oral doses of 30-120 mg HP501 were well tolerated in patients with hyperuricemia with or without gout.Pharmacokinetic analysis showed that HP501 exposure increased with an increase in the administration dose from 30 to 120 mg.However, pharmacodynamic analysis revealed that the serum UA decline was saturated at the 90 mg dose level.Thus, 90 mg HP501 is recommended for subsequent clinical studies of this highly selective URAT1 inhibitor.

Figure 1 .
Figure 1.Patient enrollment and treatment assignments.

Figure 2 .
Figure 2. Mean plasma concentrations of HP501 at each time point.(a) Linear coordinate; (b) semilog coordinate.The error bar indicates the standard deviation.

Figure 3 .
Figure 3.Comparison of pharmacokinetic parameters among five cohorts.(a) peak plasma concentration (C max ); (b) area under the concentration-time curve from time zero to infinity (AUC 0-∞ ); (c) maximal concentration during one dosing interval τ at steady state (C max,ss ); (d) area under the concentration-time curve during one dosing interval τ at steady state (AUC τ ).

Figure 4 .
Figure 4. Mean percentage change from baseline in serum UA at each time point.The error bar indicates the standard deviation.UA, uric acid.

Table 1 .
Demographic and baseline characteristics of the study patients.BMI Body mass index; UA Uric acid; SD Standard deviation.

Table 3 .
Summary of adverse events.AE Adverse event; ADR Adverse drug reaction.

Table 4 .
Pharmacokinetic parameters of HP501 in single dose period.C max Maximum plasma concentration; AUC 0-24 h

Table 5 .
Pharmacokinetic parameters of HP501 in multiple doses period.C max,ss Maximal concentration during one dosing interval τ at steady state; C min,ss Minimum concentration during one dosing interval τ at steady state; AUC 0-72 h The area under the plasma concentration-time curves from 0 to 72 h; AUC 0-∞ The area under the plasma concentration-time curves from time zero to infinity; AUC τ Area under the concentrationtime curve during one dosing interval τ at steady state; T max Time to peak plasma concentration; T 1/2 Terminal elimination phase half-life; CL/F Clearance rate; Vz/F Apparent volume of distribution at terminal phase; Rac Accumulation ratio.a expressed as mean (standard deviation).b expressed as median (range).

Table 6 .
The number of patients achieving a serum UA level ≤ 360 μmol/L at each time point on Day 13 [n (%)].